Chiral versus achiral crystal structures of 4-benzyl-1H-pyrazole and its 3,5-diamino derivative

Despite the facile interconversion of its conformers in solution, 4-benzyl-1H-pyrazole adopts a chiral crystal structure (space group P21). Its 3,5-diamino derivative, however, crystallizes in the centrosymmetric space group P21/c. In both crystal structures, the aromatic moieties are organized in alternating bilayers in which they stack in parallel columns in two orthogonal directions, and the pyrazole units form catemer motifs by N—H⋯N and N—H⋯π hydrogen bonding, respectively.


Chemical context
1H-Pyrazole (pzH) is a chemically and thermally robust organic molecule (Katritzky et al., 2010).Hence, its functionalized derivatives have found widespread applications as pharmaceuticals, pesticides and dyes (Ahmed et al., 2016 and references therein).Owing to its adjacent pair of N atoms, pyrazole derivatives are also very popular in coordination chemistry, especially for the construction of discrete polynuclear complexes (Al Isawi et al., 2021 and references therein).Within the crystal packing of pyrazole derivatives with different substituents, N-H� � �N hydrogen bonding between pz moieties leads to either discrete hydrogen-bonded motifs, such as dimers, trimers, tetramers and hexamers, or polymeric catemers depending on the substituents (Alkorta et al., 2006;Bertolasi et al., 1999;Cammers & Parkin, 2004;Claramunt et al., 2006;Foces-Foces et al., 2000).In general, the overall crystal structure is the result of the interplay of optimal shape packing and multiple different intermolecular forces, including electrostatic interactions, hydrophobic effects, aromatic interactions, hydrogen bonding with potential hydrogen-bond donor/acceptor substituents, halogen bonding and other non-covalent interactions.

Structural commentary
Displacement ellipsoid plots of the crystal structures of 1 and 2 are shown in Figs. 1 and 2, respectively.Similarly to the parent pyrazole (La Cour & Rasmussen, 1973;Sikora & Katrusiak, 2013) and 4-fluoropyrazole (Ahmed et al., 2023), the NH and N centers of the pz rings in 1 and 2 are not disordered and two distinct sets of C-N and C-C bond distances are observed.Thus, the C-N bond adjacent to N is shorter than the one adjacent to NH, whereas the C-C bond adjacent to N is longer than the one adjacent to NH (see supporting information).This is in contrast with other pyrazole derivatives, such as 4-phenylpyrazole (Reger et al., 2003) and 4-halopyrazoles (halogen = Cl, Br, I; Rue & Raptis, 2021;Foces-Foces et al., 1999;Rue et al., 2023), where the N-H hydrogen atom is disordered over the two N atoms of the pyrazole unit.Otherwise, the N-N, C-N and C-C bond lengths in 1 and 2 are similar to those observed in related pyrazole derivatives.C-C-C bond angles between the pz, CH 2 and Ph units are 63.85 (15) � in 1 and 65.65 (9) � in 2, with pz/Ph centroidcentroid distances of 4.8294 (10) and 4.7376 (9) A ˚, respectively.While the dihedral angles between the pz and Ph units in 1 and 2 are not very disparate [86.00 (7) and 65.27 ( 4) � ], the corresponding individual fold and twist angles are rather different.Specifically, the fold angle is much smaller in 1 [17.52 ( 12) � ] than in 2 [76.12 (8) � ], whereas the twist angle is much larger in 1 [65.00 ( 4) � ] than in 2 [7.42 (6) An interesting difference between the structures of 1 (P2 1 ) and 2 (P2 1 /c) is related to their crystal symmetry.Although 4-benzyl-1H-pyrazole displays axial chirality (atropisomerism; Basilaia et al., 2022) in the crystal structure described here, the two atropenantiomers can interconvert in solution by rotation of the benzyl substituent around the C(pz)-C(CH 2 ) single bond (Fig. 3).Even if the direct conversion of conformer A to conformer B by rotation of the benzyl group from one side to   the other side of the pz moiety would meet a significant barrier (caused by bulky substituents on the pz ring), A can still convert to B through its annular tautomer C. The latter converts to B by a same-side rotation of the benzyl group.Despite the facile interconversion of its different conformers (A-D), evidenced by a single resonance for the two pyrazole C-H protons in its 1 H NMR spectrum (Fig. 4), 1 adopts a chiral crystal structure (in the achiral, yet non-centrosymmetric space group P2 1 ; Flack, 2003).This must be the result of a more efficient crystal packing in the non-centrosymmetric space group (detailed in the next section) than in a centrosymmetric one.

Supramolecular features
The pz moieties in 1 are organized into layers along the ab plane, which consist of two symmetry-related (by a 2 1 screw axis) halves (Fig. 5).Within each half, the pz moieties are all parallel to each other (crystallographically imposed) and are organized into parallel columns along both the a and b axes (which are orthogonal), with pz-pz interplanar distances of 3.540 (4) and 2.184 (5) A ˚, and centroid-centroid distances of 5.6651 (5) and 5.7566 (6) A ˚, respectively.The two halves of the pz layer are connected by edge-to-face pz-pz interactions with dihedral angles of 44.59 (11) � and centroid-centroid distances of 4.3813 (12) A ˚(closest H� � �pz-plane and H� � �pzcentroid distances: 2.7021 (8) and 2.7052 (8) A ˚), as well as by N-H� � �N hydrogen bonding between pz moieties (Table 1), which leads to catemers along the b axis with pz/pz dihedral angles of 44.59 (11) � and centroid-centroid distances of 4.3813 (12) A ˚).
In 2, the pz moieties form layers along the bc plane, which are comprised of two 2 1 screw axis-related halves as in 1 (Fig. 6).Here, however, the pz moieties are only parallel within individual columns and in every second column, with dihedral angles between neighboring inter-columnar pz moieties of 85.71 ( 7
Similarly to 1, the phenyl moieties of 2 form layers but along the bc plane, which are analogous to the layers formed by its pz moieties with dihedral angles of 85.07 (6) � between neighboring inter-columnar Ph moieties [centroid-centroid distance: 6.0946 (8) A ˚]. Within each column, the Ph-Ph interplanar and centroid-centroid distances are 3.4833 (18) and 4.7271 (7) A ˚, respectively.Because the Ph moieties in neighboring columns are not parallel, two types of Ph-Ph interactions are present between the two halves of the Ph layer.Edge-to-face interactions are characterized by dihedral angles of 85.07 (6) � and centroid-centroid distances of 5.4925 (10) A ˚[closest H� � �Ph-plane and H� � �Ph-centroid distances: 2.8014 (3) and 3.4126 (6) A ˚], in addition to offset stacked interactions between parallel Ph moieties with interplanar and centroid-centroid distances of 1.997 (3) and 6.0466 (13) A ˚, respectively.
Not only does 3 crystallize in the same space group as 1, but it also adopts a very similar crystal packing in a unit cell of comparable dimensions [a = 6.2303 (6) A ˚; b = 5.5941 (5) A ˚; c = 15.1364(15) A ˚; � = 97.049(1) � ].Notably, its c axis is longer than in 1 [13.2321(9) A ˚] to accommodate the bulkier CH 3 group compared to H.The C-C-C bond angle of 66.3 (3) � between the pz, CH 2 and Ph units is closer to that of 2 [65.65 (8) � ], with a pz/Ph centroid-centroid distance of 4.6524 (2) A ˚, shorter than in both 1 and 2. The dihedral angle of 78.65 (13) � between the pz and Ph units in 3 is in-between the values of 1 and 2, with individual fold and twist angles of 60.60 (14) and 52.27 (16) � .
The supramolecular features of 3 are similar to those of 1, with a slightly expanded crystal packing due to the presence of the CH 3 groups.Thus, the parallel columns along the a and b axes feature pz-pz interplanar distances of 2.995 (8) and 3.514 (7) A ˚, and centroid-centroid distances of 6.2303 (6) and 5.5941 (5) A ˚, respectively.The edge-to-face orientation of the pz/pz pairs within the two halves of the pz layer is described by a dihedral angle of 77.83 (18) � and centroid-centroid distance of 5.8969 (19) A ˚, which are significantly larger than the corresponding values in 1 [44.59 (11) � and 4.3813 (12) A ˚].The N-H� � �N hydrogen bonding between pz moieties leading to catemers along the b axis is characterized by N-H, H� � �N and N� � �N distances of 0.86, 2.09 and 2.946 (4) A ˚, with an N-H� � �N angle of 170 � , pz/pz dihedral angle of 77.83 (18) � and centroid-centroid distance of 4.9789 (19) A ˚.The corresponding values for the Ph-Ph interactions along the a and b axes are 2.202 (11) and 3.772 (7) A ˚(interplanar) and 6.2302 (6) and 5.5941 (5) A ˚(centroid-centroid), whereas between the two halves of the Ph layer the values are 84.8 (2) � (dihedral angle) and 5.066 (3) A ˚(centroid-centroid), with closest H� � �Ph-plane and H� � �Ph-centroid distances of 2.863 (3) and 3.1738 (17) A ˚. Similarly to 1, the methyl and benzyl protons are involved in various C-H� � �� interactions with neighboring pz and Ph moieties.3,5-Diphenyl-4-benzyl-1H-pyrazole (4) crystallizes in the centrosymmetric space group P2 1 /c.As opposed to 1-3, however, the N-H� � �N hydrogen bonding between pz moieties does not lead to catemers.Instead, 4 forms hydrogenbonded dimers, with an overall crystal packing very different from the ones of 1-3.

Synthesis and crystallization
4-Benzyl-1H-pyrazole (1) was synthesized by reduction with hypophosphorous acid of 3,5-diamino-4-benzyl-1H-pyrazole (2) (Echevarrı ´a & Elguero, 1993), which in turn was obtained from benzylmalononitrile by reaction with hydrazine hydrate (Vaquero et al., 1987).The synthesis of benzylmalononitrile by alkylation of malononitrile with benzyl bromide provided the monobenzylated product contaminated with large amounts of dibenzylated side product (Dı ´ez- Barra et al., 1991).Therefore, an alternate method, by the reaction of malononitrile with benzaldehyde and reduction of the benzylidenemalononitrile intermediate with NaBH 4 was used for the preparation of pure benzylmalononitrile in high yield (Tayyari et al., 2008).Single crystals were grown by recrystallization from hot n-heptane (1) or by vapor diffusion of benzene into a solution in pyridine at room temperature (2).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. C-H bond distances were constrained to 0.95 A ˚(pz and Ph) or 0.99 A ˚(CH 2 ) and refined as riding.Positions of N-bound H atoms were freely refined.U iso (H) values were set to 1.2 or 1.5 times U eq (C/N) for H atoms.  T min = 0.605, T max = 0.754 4021 measured reflections 1612 independent reflections 1549 reflections with I > 2σ(I)

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Figure 3
Figure 3Interconversion between the different conformers, tautomers and atropenantiomers of 4-benzyl-1H-pyrazole (A-D) by annular tautomerism and/or rotation of the benzyl moiety (red: above pz plane; blue: below pz plane) around the C-C bond between the pz and CH 2 units.

Figure 4 1H
Figure 41 H NMR spectra of 1 in CDCl 3 (upper) and 2 in DMSO-d 6 (lower) at ambient temperature.The signal for the NH proton of 1 is not detectable due to exchange with the solvent deuterium.

Table 3
Experimental details.